ABSTRACT

Study question: Is ovarian stimulation with follitropin delta in its individualised fixed-dose regimen at least as efficacious as follitropin alfa in a conventional dosing regimen in Asian population?

Summary answer: Ovarian stimulation with individualised follitropin delta dosing resulted in a non-inferior ongoing pregnancy rate (primary endpoint), a significantly higher live birth rate (secondary endpoint) and a significantly lower incidence of early ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions (secondary endpoints) compared to conventional follitropin alfa dosing.

What is known already: Previous randomised controlled trials conducted in Japan as well as in Europe, North and South America have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum anti-Müllerian hormone (AMH) level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates.

Study design, size, duration: Randomised, controlled, multi-centre, assessor-blind trial conducted in 1,009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Randomisation was stratified by age (<35, 35–37, 38–40 years).

Primary endpoint: The primary endpoint was ongoing pregnancy rate assessed 10–11 weeks after embryo transfer in the fresh cycle (non-inferiority limit -10.0%; analysis adjusted for age stratum).

Secondary endpoints:

• Efficacy secondary endpoints included pregnancy outcomes such as positive bhCG rate, clinical pregnancy rate, ongoing implantation rate, live birth rate and live birth rate at 4 weeks after birth.
• Ovarian response parameters included number of oocytes retrieved, ovarian response within 8–14 oocytes, excessive ovarian response in at-risk population, endocrine profile at end-of-stimulation, fertilisation rate, number of embryos on day 3 after oocyte retrieval, average daily dose of gonadotropin, total gonadotropin dose and duration of stimulation.
• Safety evaluations included adverse events, early OHSS, preventive interventions for early OHSS, late OHSS and injection site reactions.

Participants/materials, setting, methods: The follitropin delta treatment consisted of a fixed daily dose individualised according to each patient’s initial AMH level and body weight (AMH <15 pmol/l: 12 μg; AMH ~15 pmol/l: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The follitropin alfa dose was 150 IU/day for the first 5 days with subsequent potential dose adjustments according to individual response. A gonadotropin-releasing hormone (GnRH) antagonist protocol was applied. OHSS was classified based on Golan’s system. Women with an ongoing pregnancy were followed until live birth and 4 weeks after.

Main results and the role of chance: The number of oocytes retrieved was significantly (p<0.001) lower with individualised follitropin delta versus conventional follitropin alfa (10.0±6.1 versus 12.4±7.3). Nevertheless, compared to the conventional dosing approach, the individualised follitropin delta dosing regimen resulted in on average 2 more oocytes (9.6±5.3 versus 7.6±3.5) in potential low responders as indicated by AMH <15 pmol/l, and on average 3 fewer oocytes (10.1±6.3 versus 13.8±7.5) in potential high responders as indicated by AMH ≥15 pmol/l. Among women with AMH ≥15 pmol/l, excessive response occurred less frequently with individualised follitropin delta than with follitropin alfa (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%; both p<0.001). The incidence of early OHSS and/or preventive interventions for early OHSS was significantly (p=0.004) reduced from 9.6% with follitropin alfa to 5.0% with individualised follitropin delta. The total gonadotropin use was significantly (p<0.001) reduced from an average of 109.9±32.9 μg (1,498±448 IU) follitropin alfa to 77.5±24.4 μg follitropin delta. Non-inferiority of follitropin delta in its individualised dosing regimen to conventional follitropin alfa was established with respect to the primary endpoint of ongoing pregnancy rate which was 31.3% with follitropin delta compared with 25.7% with follitropin alfa (estimated mean difference 5.4% [95% CI: -0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with individualised follitropin delta compared with 24.7% with follitropin alfa (estimated mean difference 6.4% [95% CI: 0.9%; 11.9%]; p=0.023). The live-birth rates for each stratum were as follows for follitropin delta and follitropin alfa, respectively; <35 years: 31.0% versus 25.0%, 35–37 years: 35.3% versus 26.7%, 38–40 years: 20.0% versus 14.3%.

Limitations, reasons for caution: The trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers.

Wider implications of the findings: The present trial shows that in addition to reducing the early OHSS risk (secondary endpoint), follitropin delta in its individualised fixed-dose regimen has the potential to improve the success rate in fresh cycles across all ages and with a lower gonadotropin consumption compared with conventional follitropin alfa dosing (secondary endpoint).

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